Uconn Scientists Find New Path To Long Life

Fruit Flies Provide Another Clue To Mystery Of Aging

They didn't disarm the grim reaper, but scientists at the University of Connecticut Health Center managed to blunt his blade a bit.

By introducing mutations into a single gene, UConn scientists nearly doubled the average life span of the common fruit fly, the researchers reported in today's edition of the journal Science.

The flies with the mutated gene, a gene humans also possess, stayed frisky and fertile longer than genetically unaltered peers.

The research also shed more light on the mystery of aging, a process science has been able to slow in a growing number of cases.

``The UConn group has demonstrated that single genes can have a profound effect on maximum life span,'' said Dr. Raj Sohal, professor of molecular pharmacology and toxicology at the University of Southern California. ``The magnitude of the change is astounding.''

Unaltered Drosophila flies lived an average of 37 days. But when five different mutations were introduced into the gene, the average life span of the flies increased to about 70 days.

The life span increase of the UConn flies was dramatically longer than the 35 percent average increase attributed to Methuselah, the first Drosophila gene shown to increase longevity.

The new gene had other benefits. Female flies reproduced 40 percent longer, and all flies with mutations stayed physically active longer than flies in control groups.

The longest-living flies with altered genes survived 110 days, about 50 percent longer than the the oldest of their unaltered peers.

The prolonged laboratory death watch for the flies inspired lead author Dr. Stephen Helfand, associate professor of genetics and developmental biology, and his co-author and departmental colleague Robert Reenan to name the gene Indy, for ``I'm Not Dead Yet.''

The line is uttered in the movie ``Monte Python and the Holy Grail'' by a plague victim who objects to being hauled off prematurely for his own burial.

The UConn research team stumbled upon the Indy gene by sheer chance. They were trying to find out which genes in the Drosophila stay active and which shut down as the fly ages. They noticed that the same pattern of gene activity turned up in two of about 1,000 strains of flies they were testing.

The two lines were both long-lived and, to the surprise of researchers, both had mutations of the same gene.

Investigators Helfand, Reenan and Assistant Professor Blanka Rogina believe the gene plays a role in the metabolism of the fly. They suspect that the Indy mutations affect how the fly processes food and may induce a condition known as caloric restriction.

Although scientists don't know why, severely restricting calories substantially prolongs the life of members of several species -- without limiting their physical activity.

``It's a huge leap, but if we can do that, the story gets very interesting,'' Helfand said. ``It means we've managed to create a genetic caloric restriction.''

Because the same gene exists in humans, the UConn research suggests it may be plausible to design drugs that would enable people to live longer.

Sohal said the UConn research fits well with other theories about aging, such as the damaging effects on human organs of free radicals, the byproducts of energy use. Food calories are the fuel of that energy.

Evolutionary biologistscaution, however, that it is unlikely that Indy, or any single gene, will allow mankind to stay thin and reproduce longer than it does now.

There is no free lunch in nature because every benefit to an organism carries a cost that could reduce its odds in the survival sweepstakes, said Marc Tatar, an evolutionary biologist at Brown University.

He said during hundreds of millions of years of evolution such a huge genetic advantage -- like the ability to reproduce 40 percent longer as reported in the UConn flies -- probably would have been created and preserved in nature -- unless it had other significant drawbacks.

That cost, which would have reduced the fly's ability to transmit its genes to the next generation, might stay hidden in the cozy confines of a laboratory, but be revealed if the fly were exposed to the rigors of life in nature, Tatar said.

``You'd expect to see a cost associated with a mutant in different environmental conditions,'' Tatar said.

Helfand agreed that the Indy mutations were created in the laboratory, not in nature. However, he noted that humans no longer depend upon the same set of genes they did when they were hunting or scavenging on the African savanna.

``The truth is, we still don't know much about aging,'' he said.

But Helfand and others are beginning to suspect that physical decline may not be inevitable.

Helfand, quoting Nobel Prize-winning physicist Richard Feynman, said: "It is one of the most remarkable things that in all of the biological sciences, there is no clue as to the necessity of death.''